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Characterization of L-aminocarnitine, an inhibitor of fatty acid oxidation.
[zellweger syndrome]
The
pathogenesis
of
hypoketotic
hypoglycemia
and
cardiomyopathy
in
patients
with
fatty
acid
oxidation
(
FAO
)
disorders
is
still
poorly
understood
.
In
vitro
studies
are
hampered
by
the
lack
of
natural
mutants
to
asses
the
effect
of
FAO
inhibition
.
In
addition
,
only
a
few
inhibitors
of
FAO
are
known
.
Furthermore
,
most
inhibitors
of
FAO
are
activating
ligands
of
peroxisome
proliferator-activated
receptors
(
PPARs
)
.
We
show
that
l-aminocarnitine
(
L-AC
)
,
a
carnitine
analog
,
inhibits
FAO
efficiently
,
but
does
not
activate
PPAR
.
L-AC
inhibits
carnitine
palmitoyltransferase
(
CPT
)
with
different
sensitivities
towards
CPT
1
and
CPT
2
,
as
well
as
carnitine
acylcarnitine
translocase
(
CACT
)
.
We
further
characterized
L-AC
using
fibroblasts
cell
lines
from
controls
and
patients
with
different
FAO
defects
.
In
these
cell
lines
acylcarnitine
profiles
were
determined
in
culture
medium
after
loading
with
[
U-
(
13
)
C
]
palmitic
acid
.
In
control
fibroblasts
,
L-AC
inhibits
FAO
leading
to
a
reduction
of
C
2
-
acylcarnitine
and
elevation
of
C
16
-
acylcarnitine
.
In
very
long
-chain
acyl-
CoA
dehydrogenase
(
VLCAD
)
-
deficient
fibroblasts
,
L-AC
decreased
the
elevated
C
14
-
acylcarnitine
and
increased
C
16
-
acylcarnitine
.
In
CACT
and
CPT
2
-
deficient
cell
lines
,
L-AC
did
not
change
the
already
elevated
C
16
-
acylcarnitine
level
,
showing
that
CPT
1
is
not
inhibited
.
Oxidation
of
pristanic
acid
was
only
partly
inhibited
at
high
L-AC
concentrations
,
indicating
minimal
CACT
inhibition
.
Therefore
,
we
conclude
that
in
intact
cells
L-AC
inhibits
CPT
2
.
Combined
with
our
observation
that
l-
AC
does
not
activate
PPAR
,
we
suggest
that
L-AC
is
useful
to
simulate
a
FAO
defect
in
cells
from
different
origin
.
Diseases
Validation
Diseases presenting
"lack of natural mutants"
symptom
zellweger syndrome
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